Project Summary/Abstract (Core C, Krogan) Core C of this renewal of NIH 5P01AI063302-12 will apply innovative proteomics approaches to study the early immune response to bacterial infection. Using mass spectrometry-based approaches, we will analyze macrophages infected with three different bacteria (L. monocytogenes, L. pneumophila, and M. tuberculosis) to identify the host and bacterial proteins that are ubiquitylated or phosphorylated during infection. This work will provide a comprehensive, global view of the posttranslational landscape during early infection, how these events influence host and pathogen defenses, and how these events vary across bacterial species. These global studies will dovetail with other, more targeted studies that employ host and bacterial mutants to perturb specific pathways and proteins. We will employ innovative and powerful modeling approaches to map and integrate this data to uncover the complex functions and pathways that are a part of the immune system's ability to detect and thwart bacterial pathogenesis, and the specific ways in which the pathogens are able to disrupt these mechanisms. The core's analysis and modeling work will serve three experimental Projects and will integrate the effort of each, providing a unified vision of the Program's results.